Multiparticulate L-menthol formulations and related methods

ABSTRACT

A multiparticulate formulation includes a plurality of individual spheroidal enteric coated cores containing L-menthol from an at least 80% pure L-menthol source. A subcoat is beneath the enteric coat. The enteric coated cores have a diameter of not more than 3 mm. The multiparticulate formulation may be used to treat gastrointestinal disorders, such as irritable bowel syndrome.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 13/367,747, filed Feb. 7,2012, now U.S. Pat. No. 8,568,776, which claims priority to App. No.61/441,716 filed Feb. 11, 2011 entitled “Multiparticulate Formulationsand Related Methods,” and App. No. 61/486,523, filed May 16, 2011entitled “Multiparticulate Formulations and Related Methods.” Each ofthese prior applications is incorporated by reference herein in itsentirety.

FIELD OF THE INVENTION

The invention relates to multiparticulate formulations for deliveringhigh purity L-menthol to the intestines, and, more particularly, toenteric coated high purity L-menthol multiparticulate formulations andrelated methods.

BACKGROUND

Essential oils have been used for their bioactivity for quite some time.Some essential oils are currently being used as medicaments. For examplethe plants mentha piperita or mentha arvensis, are the two primarysources of peppermint oil. Peppermint oil is effective at treating thesymptoms of gastrointestinal disorders such as irritable bowel syndrome(IBS). These symptoms can include pain, discomfort, bloating,constipation, and/or diarrhea. Clinical trials have demonstratedsignificant alleviation of the symptoms associated with IBS through theuse of peppermint oil in single unit capsules coated with the celluloseacetate-phthalate enteric polymer or other enteric-coating polymers.

For maximal efficacy in the treatment of IBS and to avoid relatedcomplications, peppermint oil should be locally delivered to theintestines, while avoiding the stomach. If peppermint oil is releasedfrom its dosage form prior to passing through the pyloric sphincter intothe intestines, it can irritate the mucous membranes in the digestivetract. Releasing peppermint oil directly into the stomach can causeheartburn (gastric irritation) and gastro-esophogeal reflux disease.Therefore, since peppermint oil is usually administered orally, itshould preferably be prepared with an enteric coating.

Enteric-coated single unit capsules for treating irritable bowelsyndrome that contain peppermint oil currently exist. But, even thoughthe enteric coated single unit capsules are meant to delay the releaseof peppermint oil until after the capsule enters the intestines, thisapproach to treating IBS has several drawbacks. The drawbacks includepremature release of the peppermint oil from the capsule in the stomach,resulting in heartburn. Also, the accidental chewing of the capsulecauses the enteric coat to rupture prematurely and release the oil inthe stomach. Using current formulations of peppermint oil, significantdoses are required to achieve an efficacious concentration of peppermintoil in the body. For example, each of the above referenced capsulescontains about 200 mg of peppermint oil and must be taken three times aday, 30-60 minutes prior to a meal. The dose can be increased to twocapsules taken three times daily in some situations.

Enteric-coated peppermint oil is typically administered as a single-unitformulation. However, in a single-unit formulation, the amount ofpeppermint oil absorbed by the intestines can vary from dose to dose forseveral reasons. First, single-unit enteric capsule formulation can getattached to the esophagus because of the muco-adhesive properties of theenteric coat and therefore not enter the stomach within the desired timeframe. The single unit enteric coated capsules, like enteric coatedsingle unit tablets have been shown to not release the active ingredientfrom the single unit formulation because the single unit's size is toolarge to pass through the constriction in the stomach's pylorus valve.The enteric coat of the capsule may also prematurely crack or rupturebecause of the force created by the swelling of the gelatin (orhypromellose) seal coat against the thinner outer enteric coat.Peppermint oil containing capsules have a lower specific gravity thanthe stomach contents, and tend to float rather than settle and then passthrough the pylorus constriction between the stomach and the lowerintestines.

Non-disintegrating tablets or capsules given with food may stay in thestomach for long times, 10 to 15 hours, before they are emptied into thesmall intestine. Small particles, with diameters less than 3 mm, areemptied from the stomach more regularly, regardless of whether they aregiven with food. The 10 to 15 hours that an enteric coated hard gelatinor hypromellose capsule can get exposure to gastric conditions in a fedstate may cause the enteric coat to rupture and the hard gelatin (orhypromellose) seal coat to dissolve, resulting in the peppermint oilbeing released in the stomach and causing heartburn or gastricirritation.

Even when the single unit enteric coated capsule passes through thepylorus intact in a timely fashion, when it reaches the small intestinethe coating dissolves and a bolus of oil is released in the intestine.This dosage dumping, a situation in which the active ingredient isreleased and gives very high local exposure in a segment of theintestine, is also undesirable because it prevents uniform and steadyexposure of peppermint oil in the G.I. lumen. This high local exposureto one section of the G.I. lumen may actually aggravate symptoms of IBS.

Single-unit formulations are also significantly influenced by thequantity of food in the stomach. Gastric emptying rates of single unitdoses are erratic and unpredictable. Single-unit enteric-coated tabletsor capsules taken with food may stay in the stomach for many hoursbefore being emptied into the small intestine. As a result, single-unitformulations present both inter and intra-subject variability withrespect to the bioavailable concentration of active ingredient.According to regulatory guidelines, enteric-coated single-unit capsulescan never be bioequivalent with multiple-unit enteric-coated dosageforms. A single-unit enteric preparation containing peppermint oil wasdisclosed in U.S. Pat. No. 4,687,667, which is hereby incorporated byreference in its entirety except to the extent it may be inconsistentwith this application.

The currently available delayed release single unit dosage formscontaining enteric-coated peppermint oil have another limitation. Theydump their primary active ingredient, L-menthol, when the enteric layerdisintegrates. The terminal half life of L-menthol is ˜1.34 hours.Therefore, the systemic exposure of L-menthol is limited toapproximately 4 hours, resulting in the need for frequent (usually threetimes a day) to relieve the symptoms of IBS. The use of a single unitnon-disintegrating delayed release dosage form is undesirable due tounpredictable absorption and longer residence time in the stomach.

SUMMARY

An aspect of the invention is to provide a L-menthol multiparticulateformulation with an enteric coating, using high-purity L-menthol.

In one embodiment, the multiparticulate formulation comprises aplurality of particulates having a reduced release under gastricconditions and an elevated release at neutral pH. The particulatescomprise a core comprising L-menthol as an active ingredient. TheL-menthol is supplied to the core as an at least 80% pure L-mentholmaterial, such as a purified L-menthol containing liquid or L-mentholcrystals. An enteric coating is over the core. The enteric coating iseffective to release at least about 80% of the L-menthol within abouttwo hours of being placed in a substantially neutral pH environment.

In another embodiment, the core comprises about 30% to about 70% w/wL-menthol, about 25% to about 60% w/w microcrystalline cellulose, about0.5% to about 4% w/w hypromellose, about 1% to about 3% w/w polysorbate80, about 2% to about 15% w/w colloidal silica, about 4% to about 6% w/wcroscarmellose sodium, and about 0.5% to about 4% w/w ascorbic acid. Asub-coating comprising hypromellose is on the core. An enteric coatingis on the sub-coating. Also, the particulates have an average diameterof not more than 3 mm.

The invention also provides methods of making the multiparticulateformulations. An exemplary method of making an L-mentholmultiparticulate formulation of the invention comprises preparing aplurality of cores comprising crystalline L-menthol as an activeingredient, drying the cores, coating the cores with an enteric coatingeffective to release at least about 80% of the L-menthol within abouttwo hours of being placed in a substantially neutral pH environment; anddrying the enteric coated cores. In a particularly preferred embodimentthe temperature of the cores and enteric coated cores is maintained ator below about 30° C.

These and other objects, aspects, and advantages of the presentinvention will be better appreciated in view of the drawings andfollowing description of certain embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the dissolution of various samples ofmultiparticulate formulations of the invention in a 0.1 HCl solution(acid stage) and subsequently a pH=6.8 buffer (buffer stage).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

In the Summary above and in the Detailed Description of CertainEmbodiments and in the accompanying drawings, reference is made toparticular features (including method steps) of the invention. It is tobe understood that the disclosure of the invention in this specificationincludes all possible combinations of such particular features. Forexample, where a particular feature is disclosed in the context of aparticular aspect or embodiment of the invention, that feature can alsobe used, to the extent possible, in combination with and/or in thecontext of other particular aspects and embodiments of the invention,and in the invention generally.

The term “comprises” is used herein to mean that other ingredients,steps, etc. are optionally present. When reference is made herein to amethod comprising two or more defined steps, the steps can be carried inany order or simultaneously (except where the context excludes thatpossibility), and the method can include one or more steps which arecarried out before any of the defined steps, between two of the definedsteps, or after all of the defined steps (except where the contextexcludes that possibility).

In this section, the invention will be described more fully withreference to the accompanying drawing. This invention may, however, beembodied in many different forms and should not be construed as limitedto the embodiments set forth herein. Rather, these embodiments areprovided so that this disclosure will convey preferred embodiments ofthe invention to those skilled in the art.

The efficacy of peppermint oil in controlling smooth muscle contractioncan be substituted by its main bio-active constituent, L-menthol.Peppermint oil derived from Mentha piperita only contains up to 50%menthol and Mentha arvensis contains only approximately 70-80% menthol.The other components of peppermint oil include menthone, pulegone,menthofuran, and limone, which may cause undesirable side effects ordiminish the effectiveness of the L-menthol. In contrast to peppermintoil, which is primarily available as a liquid, L-menthol is available ina liquid and crystalline powder form. The inventors have advantageouslydeveloped a unique combination of ingredients and processing methods forproviding an enteric coated multiparticulate formulation comprising highpurity liquid or solid L-menthol.

One aspect of the invention is to provide a multiparticulate formulationcomprising solid L-menthol for treating gastrointestinal disorders suchas gastrointestinal discomfort and irritable bowel syndrome. This isadvantageous over typical peppermint oil formulations because theundesirable menthone, pulegone, menthofuran, and limone are notco-administered with L-menthol to a patient who takes the formulation,thus preventing the undesirable side effects or reduced efficacy ofL-menthol that may result.

Further, because it is desirable for L-menthol to be released into theintestines as opposed to the stomach, the formulation provides a reducedrelease in the stomach and an elevated release at a substantiallyneutral pH, such as the pH found in the intestines. In a preferredembodiment, the formulation allows for release of at least about 80% ofthe L-menthol within about two hours of being placed in a substantiallyneutral pH environment. As used herein, a substantially neutral pHenvironment means an environment having a pH of about 7, including, butnot limited to a pH of between about 6.5 to about 7.5, also includingthe pH environment of the intestines. In another preferred embodiment,the formulation allows for the release of no more than about 10% of theL-menthol within about 2 hours of being placed in a 0.1 N HCl solutionand, subsequently, no less than about 85% of the L-menthol within about45 minutes of being placed in a substantially neutral pH environment,which is consistent with USP 711 enteric protection specifications.

The solid L-menthol multiparticulate formulations of the inventionprovides an advantageous L-menthol oral delivery vehicle that can beadministered to a patient. A multiparticulate formulation of theinvention comprise a plurality of individual particulates that arepreferably spheroidal in shape and are preferably configured forincorporation into a capsule or packet-type oral delivery dosage form.

The invention also provides a unique method of making themultiparticulate formulations in which the temperature of the formationprocess is controlled and the enteric coating material chosen to preventL-menthol from significantly volatilizing or degrading, thereby allowingthe formulation of the invention to comprise L-menthol supplied from ahigh purity L-menthol source such as a purified liquid L-menthol orsolid L-menthol preferably at or above 80% purity.

The data provided in the examples section show that the inventors havesuccessfully produced a high purity enteric coated multiparticulateL-menthol composition with a dissolution profile consistent with USP 711specifications. This formulation allows for prolonged duration ofaction, more reliable dosing, and reduced drawbacks from the undesirableL-menthol derivatives or degradants when compared to current marketedpeppermint oil formulations.

The multiparticulates of the invention comprise a plurality ofparticulates which are preferably spheroidal in shape. Each particulateis sized to fit through the pyloric sphincter in a relaxed state. Thediameter of the particulates is preferably in the range of about 0.1-3mm, more preferably about 1-2.5 mm.

The particulates are comprised of a preferably spheroidal core with anenteric coating over the core. The particulates may also have anoptional sub-coating between the core and enteric coating. In apreferred embodiment, the sub-coating comprises hydroxypropyl methylcellulose, also known as “HPMC” or “hypromellose.” The particulates mayalso include one or more additional coatings such as a sealant coatingor a color coating on the enteric coating. In a preferred embodiment,the sub-coating is hypromellose E5. The sub-coating is preferablybetween about 1-5% w/w of the enteric coated particulate.

The core comprises the primary active ingredient, which is high purityL-menthol such as solid L-menthol. Solid L-menthol is a crystallinematerial at room temperature, has a melting point at standard pressureof about 42°-45° C., and may undergo sublimation at slightly above roomtemperature. The core may also comprise an antioxidant, which canmaintain the purity of the L-menthol to prevent the L-menthol fromoxidizing into undesirable derivatives. Examples of antioxidantsinclude, but are not limited to tocopherol (vitamin E,) BHT (butylatedhydroxy toluene), BHA (butylayted hydroxy anisole), and ascorbic acid.The core may also comprise one or more inactive ingredients.

The term “solid L-menthol” means L-menthol in its solid form, preferablyin its crystalline form. In the crystalline form, L-menthol issubstantially free of undesirable impurities. Although it may not alwaysbe necessary, it is preferred that the starting material for L-mentholappear as visually perceptible L-menthol crystals that are then groundinto a polycrystalline powder. During development of the formulation ofthe invention, the inventors found that micronizing the L-mentholproduced good results. Although not intending to be bound by theory, itis believed that micronizing the L-menthol produces more L-mentholsurface area, which improves L-menthol's aqueous solubility. It ispreferred, however, that the L-menthol be micronized without raising thetemperature of the L-menthol enough to degrade the L-menthol molecules,cause L-menthol to melt, or cause L-menthol to undergo sublimation. Asuitable technique for producing micronized L-menthol crystals involvesjet milling. A preferred concentration of L-menthol in the core isbetween about 30% to 70% w/w of the total enteric coated particulate.

The core may also include one or more of filler, stabilizer, binder,surfactant, processing aid, or disintegrant. By way of example only,suitable materials for performing these functions are provided. Asuitable filler includes a pharmaceutically suitable filler. In oneembodiment, the filler is microcrystalline cellulose. A suitable binderincludes a pharmaceutically suitable binder. In a preferred embodiment,the binder is a cellulosic water soluble polymer such as celluloseether. Because L-menthol is not highly soluble in water, it may beadvantageous to include a surfactant as a solubilizing agent. Apreferred solubulizing agent is polysorbate 80 or sodium lauryl sulfate(“SLS”). It was discovered that the solubilizing agent improved thewettability and, therefore, the rate and extent of release of L-mentholfrom the particulates. Polysorbate 80 also enhances absorption ofL-menthol into the plasma.

A suitable processing aid includes a pharmaceutically suitableprocessing aid such as for improving the flowability of the corematerials during processing. In a preferred embodiment, the processingaid is colloidal silicon dioxide.

A suitable disintegrant includes a pharmaceutically suitabledisintegrant. In a preferred embodiment, the disintegrant iscroscarmellose sodium.

A preferred composition for the core comprises about: 30-70% w/wmicronized L-menthol; about 2% to 15% w/w processing aid; about 25 to60% w/w filler; about 4% to 6% w/w disintegrant; about 0.5% to 4% w/wbinder; about 1% to 3% w/w solubilizing agent; and about 0.5% to 4% w/wantioxidant. Here the % w/w is relative to the total weight of theenteric coated particulate.

A listing of ingredients for two exemplary embodiments of the core isshown in Table 1. In Table 1, the % w/w is based on the uncoated core.For Core 1, L-Menthol was supplied as 95% w/w L-Menthol/5% w/w CAB-O-SILM5P (Silicon Dioxide) and was milled using Fitz Mill equipment. For Core2, L-Menthol was supplied as 95% w/w L-Menthol/5% w/w CAB-O-SIL M5P(Silicon Dioxide) and was milled using Jet Pulverizer equipment. The %represents the theoretical quantity of L-Menthol in the blend. Core 1used AVICEL PH-101 as the filler and Core 2 used AVICEL PH-102 as thefiller. These are chemically identical microcrystalline cellulose andvary only by particle size.

The enteric coating is applied over the uncoated core or, if thesub-coating is present, over the sub-coating. The enteric coating ispreferably applied so that it comprises about 5-35% w/w of the entericcoated particulate. A preferred enteric coating material is amethacrylic acid based material such as a methacrylic acid basedco-polymer. Examples of suitable methacrylic acid based copolymersinclude EUDRAGIT L30D-55 (poly(meth)acrylate-based coating) or KOLLICOATMAE 30 DP. KOLLICOAT® MAE 30 DP is a methacrylic acid-ethyl acrylateco-polymer. These materials may be combined with other materials such asplasticizers for forming an enteric coating solution. In a typicalembodiment, an enteric coating solution comprises about 20-40% w/wwater, about 0.5-1.5% w/w plasticizer, about 5-15% anti-adherent, andabout 40-70% copolymer. By way of example only, a suitable plasticizeris triethyl citrate and a suitable anti-adherent is PLASACRYL T20.PLASACRYL T20 is an emulsion of anti-tacking agent and plasticizer andcontains water, glyceryl monostearate, triethyl citrate and polysorbate80.

Although it may not always be necessary, it is preferred that theenteric coating material be applied to the core without heating the coreabove about 30° C. This can be particularly difficult considering thatenteric coatings are typically applied in a fluidized bed coater atsufficient air inlet temperature to result in a product temperature ofabout 38-42° C. Unfortunately, at such a high temperature, L-mentholtends to degrade and volatilize. This made it very difficult to producea high purity, solid L-menthol formulation that met or approximated thedesired USP 711 enteric specifications. The inventors found that bothEUDRAGIT L30D-55 and KOLLICOAT MAE 30 DP were suitable because theycould be reliably applied to the cores at lower temperatures with goodcoalescence between the enteric coating and the underlying material.Without intending to be bound by theory, this may be because the glasstransition temperature T_(g) of these methacrylic acid based copolymersis roughly about 26° C. and depends on the plasticizer used. Thesemethacrylic acid copolymer based enteric coating materials do notrequire pH sensitive pore formers to dissolve at or near neutral pH.

A listing of the ingredients in an exemplary embodiment of entericcoated particulates is provided in Table 2. The core in this example isCore 2. The % w/w is based on the weight enteric coated particulate.

Methods of making the multiparticulate formulations in accordance withanother aspect of the invention will now be described. The core istypically prepared by wet granulating the core materials into a wetmass, extruding the wet mass to form an extrudate, cutting the extrudateinto a plurality of core pieces, and spheronizing the core pieces. Ifthe antioxidant is in a liquid solution, the liquid antioxidant solutionmay be sprayed into the wet mass. The spheronized core pieces arepreferably dried to <3% based on the Karl Fischer method. Thespheronized core pieces are then coated with the enteric coatingmaterial. The enteric coating is typically applied in a fluidized bedcoater. The enteric coated particulates are subsequently dried, to <3%(Karl Fischer). The dried enteric coated multiparticulates may then beprepared into a suitable pharmaceutical dosage form such as a capsule ortablet, for example. A typical preferred capsule contains about 250 mgof the particulates. Depending on the desired dosage, however, this maybe adjusted.

The inventors found that L-menthol may sublimate, oxidize, or otherwisedegrade during processing if the processing parameters are not carefullycontrolled. For example, the mechanical force of granulating theL-menthol may cause it to heat, thereby resulting in sublimation,oxidation, and/or degradation. However, using a technique forgranulating the L-menthol, such as jet milling, allowed for theinventors to produce cores in which the integrity and amount of rawL-menthol was retained. Aside from issues related to granulation, dryingthe core pieces and applying the enteric coating can adversely heat theL-menthol as well. It is preferred that throughout the process, thetemperature of the formulation be maintained at or below 30° C. and,more preferably, at or below 25° C.

The multiparticulate formulations of the invention are preferablyformulated to be taken orally by a human or animal patient and to ensurethat the patient receives an effective amount of high purity L-mentholover the course of several hours after ingestion. An effective amount isan amount that is sufficient to affect a disease or process in the body.In a preferred embodiment a dose of a multiparticulate formulationprovides about 10 mg to 200 mg or, more preferably, about 90-110 mg ofL-menthol. Doses of the multiparticulate formulation may be administeredsporadically when needed for treating acute inflammations of the G.I.tract or may be administered as part of a long term regimen for treatingirritable bowel syndrome. A patient may be a human or animal patient.

Accordingly, another aspect of the invention is to provide a method oftreating a gastrointestinal disorder, the method comprisingadministering a multiparticulate formulation of the invention to thepatient (human or animal).

EXAMPLES

This section describes examples of certain preferred embodiments of theinvention. The examples are not intended to limit the scope of theinvention in any way.

Example 1 Preparation of Multiparticulate Formulations

Experimental Details.

The equipment utilized to create the formulations herein includes thefollowing: top loading balances, hand screens (12, 14, 16, 18, Pan, 70mesh), Rotap sieve shaker, IKA mixer, KitchenAid food processor(pre-milling), Fitz mill equipped with a 0.065″ screen, Jet Mill, KeyInternational high sheer mixer, Glatt GPCC-3 fluid bed drier, GlattGPCC-3 fluid bed dried with 7″ Wurster, Karl Fischer moisture analyzer,and a spheronizer.

Preparation of Core 1.

Core 1, shown in Table 1, was prepared as described above utilizing thefollowing settings. The wet granulation settings were: impeller speed300 rpm, chopper speed 3450 rpm, wet massing time 80-90 seconds, maximumImpeller Power 5.5-6.2 amps. The extrusion settings were: impeller speed25 rpm, feeder speed 30 rpm, screen size 1.2 mm. Extrudates were chargedto a spheronizer rotating at 500 rpm. Core 1 particulates were dried at17-23° C. at 45 cfm air flow for 60-75 minutes.

Preparation of Core 2.

Core 2, shown in Table 1, was prepared as described above utilizing thefollowing settings: The wet granulation setting were: impeller speed 640rpm, chopper speed 9450 rpm, maximum impeller power 6-7 amps. Theextrusion settings were: impeller speed 25 rpm, feeder speed rpm, screensize 1.2 mm. Extrudates were charged to a spheronizer rotating at900-925 rpm. Core 2 particulates were dried at 17-23° C. at 45 cfm airflow for 60-75 minutes.

Application of sub-coating.

Core 1 and Core 2 particulates were separated based on their size. Thefraction that fell within the 14-18 mesh size was chosen forsub-coating. The cores were placed into a fluidized bed dryer and thesub-coating was sprayed onto the cores in the form of a 10% hypromellose(hypromellose E5) aqueous solution that was at room temperature.

Preparation of Enteric Coating Solutions.

Two of the enteric coatings that were evaluated individually comprisedEUDRAGIT L30D-55 and KOLLICOAT MAE 30 DP. The enteric coatings wereapplied to the cores in a fluidized bed coater (7″ wurster) as a liquidsolution. Tables 3 and 4 show the ingredients used in the EUDRAGITcoating (enteric coating solution A) and the KOLLICOAT coating (entericcoating solution B), respectively.

Enteric coating solution A was applied to the cores using the followingparameters: the inlet temperature was maintained between 22.7° C. and23° C.; the exhaust temperature was maintained between 27° C. and 30°C.; the air flow was maintained between 20 and 22 cfm; the spray ratewas maintained between 4.15 and 4.4 g/min; the product temperature wasmaintained between 19° C. and 22° C.

Enteric coating solution B was applied to the cores using the followingparameters: the inlet temperature was maintained between 22.7° C. and23° C.; the exhaust temperature was maintained between 28° C. and 30°C.; the air flow was maintained between 20 and 22 cfm; the spray ratewas maintained at about 4.25 g/min; and the product temperature wasmaintained between 19° C. and 22° C.

Example 2 Evaluation of Prepared Multiparticulate Formulations

The prepared multiparticulate formulations were evaluated to determinewhether they met or approximated the desired USP 711 entericspecifications. To meet USP 711 enteric specifications, less than 10% ofthe active ingredient should be released in 2 hours in a 0.1 N HClsolution (“acid stage”). Subsequently, no less than 85% of the activeingredient should be released in 45 minutes in a pH 6.8 buffer (“bufferstage”).

The data in Tables 5 and 6 confirm that both the EUDRAGIT and KOLLICOATcoatings can successfully be used with crystalline L-menthol to formenteric coated L-menthol multiparticulate formulations that meet orapproximate USP 711 enteric specifications. In Tables 5 and 6, the batchidentification refers to the core used, the coating on the core, and thepreparation number for the specific formulation. A 3% w/w hypromellosesub-coating was applied to all of the cores before they were coated withthe specified enteric coating.

In the acid stage, the samples were placed into a 0.1 N HCl solution fortwo hours. The samples were subsequently removed from the acid stage andplaced in the buffer stage for the number of hours specified. Thenumbers indicate the % L-menthol released at the specified number ofhours.

FIG. 1 is a graph of the dissolution profile for several of themultiparticulate formulations comprising cores coated with KOLLICOAT.The % w/w of KOLLICOAT relative to the weight of the particulate wasvaried to determine which % provides the most preferred results. FIG. 1very clearly shows that the dissolution profile of the enteric coatedparticulates is much improved relative to the uncoated cores. The datafor the enteric coated multiparticulates is approximately sigmoidal inshape with a slow increase within the first two hours in the acid stageand abrupt increase after two hours once the buffer stage begins. Whenthe KOLLICOAT enteric coating is about 18% w/w of the of the weight ofthe particulate, less than 10 of the L-menthol is released in the acidstage and nearly 100% of the L-menthol is released within 2 hours in thebuffer stage.

The invention has been described above with reference to theaccompanying drawings and preferred embodiments. Unless otherwisedefined, all technical and scientific terms used herein are intended tohave the same meaning as commonly understood in the art to which thisinvention pertains and at the time of its filing. Although variousmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of the present invention,suitable methods and materials are described. The skilled shouldunderstand that the methods and materials used and described areexamples and may not be the only ones suitable for use in the invention.

Any publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety as ifthey were part of this specification. However, in case of conflict, thepresent specification, including any definitions, will control.

In the specification set forth above there have been disclosed typicalpreferred embodiments of the invention, and although specific terms areemployed, the terms are used in a descriptive sense only and not forpurposes of limitation. The invention has been described in some detail,but it will be apparent that various modifications and changes can bemade within the spirit and scope of the invention as described in theforegoing specification and as defined in the appended claims.

TABLE 1 Ingredients of two exemplary embodiments of the core. Core 1Core 2 Ingredient (grams/% w/w) (grams/% w/w) Ingredient FunctionL-Menthol 249.6/49.92 241.92/48.38 Active ingredient CAB-O-SIL M5P10.4/2.08 26.88/5.38 Processing Aid (Colloidal Silicon Dioxide) AVICEL(Micro 190.00/38.00  176.20/35.24 Filler Crystalline cellulose)AC-DI-SOL 30.00/6.00  30.00/6.00 Disintegrant (Croscarmellose Sodium)Hypromellose 10.00/1.00  10.00/1.00 Binder (METHOCEL A15 Premium)Polysorbate 80 5.00/2.00 10.00/2.00 Solubilizing Agent Ascorbic Acid5.00/1.00  5.00/1.00 Antioxidant Water (% of dry (93.00%) (86.16%) mass)

TABLE 2 Ingredients of an exemplary embodiment of enteric-coatedparticulates. Ingredient % w/w Ingredient Weight in Finished EC inFinished Ingredient Ingredient Multiparticulate Dosage Form (mg)Function L-Menthol 43.816 100.000 Active ingredient Cab-O-Sil M5P 2.8046.399 Processing (Colloidal aid Silicon Dioxide) AVICEL pH102 30.23469.001 Filler AC-DI-SOL (FMC; 5.148 11.748 Disintegrant CroscarmelloseSodium) METHOCEL A15 1.716 3.916 Binder Premium Polysorbate 80 0.8581.958 Solubilizing agent Ascorbic Acid 0.858 1.958 AntioxidantHypromellose E5 2.627 5.995 Sub-coating KOLLICOAT MAE 10.369 23.666Source of 30 DP Solids methacrylic copolymer Triethyl Citrate 0.5381.227 Plasticizer PLASACRYL T20 1.033 2.358 Anti- Adherent Water¹¹Evaporates

TABLE 3 Enteric Coating Solution A: EUDRAGIT L30D-55 (Evonik) Ingredientgrams EUDRAGIT L30D-55 (30% w/w solids) 578.7 Triethyl Citrate 9PLASACRYL T20 86.5 Water* 325.8 *Evaporates

TABLE 4 Enteric Coating Solution B: KOLLICOAT MAE 30 DP (BASF)Ingredient grams KOLLICOAT 30 DP 55 (30% w/w solids) 578.7 TriethylCitrate 9 PLASACRYL T20 86.5 Water* 325.8 *Evaporates

TABLE 5 Dissolution Results for various EUDRAGIT coated and uncoatedmultiparticulate formulations. % Dissolved per Hour Acid Stage 0.1NBuffer Stage HCl pH = 6.8 buffer Batch Time (hr) Identification 1 2 2.252.5 2.75 3 4 6 8 10 Uncoated Core 49 52 149 105 101 99 97 95 94 92 1;Preparation 1 Uncoated Core 34 41 72 77 77 76 75 75 75 74 1; Preparation2 Core 1; Evonik 2 5 35 65 77 80 86 85 85 84 EUDRAGIT L30D (12% w/w) +0.5% SLS Core 1; Evonik 2 5 42 73 83 88 91 90 90 89 EUDRAGIT L30D (12%w/w) + 1.0% SLS

TABLE 6 Dissolution Results for various KOLLICOAT coated and uncoatedmultiparticulate formulations. % Dissolved per Hour Acid Stage 0.1NBuffer Stage HCl pH = 6.8 buffer Batch Time (hr) Identification 1 2 2.252.5 2.75 3 4 Uncoated Core 2; 32 46 80 89 93 96 Preparation 1 UncoatedCore 2; 33 47 76 86 91 95 Preparation 2 Uncoated Core 2; 31 46 75 86 9195 Preparation 3 Core 2; KOLLICOAT 5 16 72 82 86 93 MAE 30 DP (12% w/w);Preparation 1 Core 2; KOLLICOAT 5 15 73 82 86 92 MAE 30 DP (12% w/w);Preparation 2 Core 2; KOLLICOAT 5 15 75 82 86 91 MAE 30 DP (12% w/w);Preparation 3 Uncoated Core 2; 36 53 80 88 92 97 Preparation 4 Core 2;KOLLICOAT 5 18 82 90 95 98 MAE 30 DP (12% w/w); Preparation 4 Core 2;KOLLICOAT 2 14 80 91 95 98 MAE 30 DP (15% w/w); Preparation 1 Core 2;KOLLICOAT 1 9 84 95 99 103 MAE 30 DP (18% w/w); Preparation 1

The invention claimed is:
 1. A multiparticulate formulation comprising aplurality of individual spheroidal enteric coated cores having adiameter of not more than 3 mm, the enteric coated cores comprisingsolid crystalline L-menthol from an at least 80% pure L-menthol sourceand a subcoat beneath the enteric coat, wherein the enteric coated coresare combined in a capsule or packet-type pharmaceutical dosage form fororal delivery.
 2. The multiparticulate formulation of claim 1, whereinthe enteric coated cores are effective to release at least 80% of theL-menthol within about 2 hours of being placed in an intestinal pHenvironment.
 3. The multiparticulate formulation of claim 1, wherein thecores further comprise a solubilizing agent effective for solubilizingL-menthol.
 4. The multiparticulate formulation of claim 1, wherein thecores further comprise an antioxidant effective for preventing theL-menthol from oxidizing.
 5. The multiparticulate formulation of claim4, wherein the antioxidant is ascorbic acid.
 6. The multiparticulateformulation of claim 1, wherein the cores comprise about 30% to about70% w/w L-menthol.
 7. The multiparticulate formulation of claim 1,wherein the enteric coated cores are effective to release no more thanabout 10% of the L-menthol within about 2 hours of being placed in a 0.1N HCl solution and, subsequently, no less than about 85% of theL-menthol within about two hours of being placed in a substantiallyneutral pH environment.
 8. The multiparticulate formulation of claim 1,wherein, in the enteric coated cores, the enteric coat is positionedover the subcoat and the subcoat is positioned over the core.
 9. Amethod of making a multiparticulate formulation, the method comprising:preparing a plurality of individual spheroidal cores by blending solidcrystalline L-menthol from an at least 80% pure L-menthol source withone or more excipients; applying a subcoat to the cores to formsubcoated cores; enteric coating the subcoated cores to form entericcoated cores; and drying the enteric coated cores to form dried entericcoated cores having a diameter of not more than 3 mm.
 10. The method ofclaim 9, wherein the dried enteric coated cores are effective to releaseat least 80% of the L-menthol within about 2 hours of being placed in anintestinal pH environment.
 11. The method of claim 9, further comprisingmixing an L-menthol solubilizing agent with the L-menthol when preparingthe cores.
 12. A method of treating a gastrointestinal disorder in asubject, the method comprising administering to the subject amultiparticulate composition comprising a plurality of individualspheroidal enteric coated cores having a diameter of not more than 3 mm,the enteric coated cores comprising solid crystalline L-menthol from anat least 80% pure L-menthol source and a subcoat beneath the entericcoat.
 13. The method of claim 12, wherein the gastrointestinal disorderis irritable bowel syndrome.
 14. The method of claim 12, wherein theenteric coated cores are effective to release at least 80% of theL-menthol within about 2 hours of being placed in an intestinal pHenvironment.
 15. The method of claim 12, wherein the cores furthercomprise a solubilizing agent effective for solubilizing L-menthol. 16.The multiparticulate formulation of claim 1, wherein the solidcrystalline L-menthol is micronized.